Several publications and patent documents are cited throughout the specification in order to describe the state of the art to which this invention pertains. Each of these citations is incorporated herein by reference as though set forth in full.
Cholestasis is the state of impaired synthesis or excretion of bile, and it is the final common endpoint of a wide variety of infectious, inflammatory, genetic, toxic, and vascular diseases of the liver. The accumulation of bile components, particularly bile acids, is toxic to the liver, and chronic cholestasis leads to progressive fibrosis, cirrhosis, liver failure, and death if untreated (Kosters et al. (2008) Xenobiotica 38:1043-71). Cholestasis is caused by a variety of infectious, obstructive, metabolic and developmental liver disorders. Advances in the understanding of the hepatic response to cholestasis may therefore have an impact on a large population of adults and children with liver disease.
Cholestasis exposes hepatocytes and cholangiocytes to elevated levels of toxins normally excreted into the small intestine, including bile acids, heavy metals, and xenobiotics. Not surprisingly, the cycle of bile acid synthesis, canalicular excretion, intestinal absorption, and import into hepatocytes is regulated by feedback mechanisms (Wagner et al. (2010) Seminars Liver Dis., 30:160-77). Most of these are based on the ability of nuclear receptor transcription factors (NRs) to detect intracellular concentrations of bile acids and other bile components. In hepatocytes, NRs repress the expression of bile acid importers and synthetic enzymes, while activating export genes. NRs primarily involved in other metabolic pathways can also influence biliary function; for example, the lipid sensor PPARγ regulates CYP7A1, the rate-limiting enzyme in bile acid synthesis, as well as the phospholipid transporter MDR3 (Mdr2 in mouse) (Marrapodi et al. (2000) J. Lipid Res., 41:514-20; Kok et al. (2003) Biochem. J., 369:539-47). Nevertheless, these homeostatic pathways are not able to protect the liver in the setting of many cholestatic diseases. As a result, cholestatic damage progresses to biliary cirrhosis and liver failure. Progress in treating patients with cholestatic disease requires a greater understanding of the molecular pathways regulating bile flow and the cellular response to chronically elevated bile acids.